Role of passive electrical properties during action potential restitution in intact heart

Action potential duration (APD) restitution is classically attributed to membrane ionic currents; however, the role of cell-to-cell coupling in restitution is poorly understood. To test the hypothesis that passive electrical properties of multicellular preparations influence restitution, spatial gradients of transmembrane voltage were measured with high spatial (0.83 mm), voltage (1 mV), and temporal (0.5 ms) resolutions using voltage-sensitive dye in Langendorff-perfused guinea pig ventricle. At short premature coupling intervals, APD failed to shorten in cells located near (< 3 mm) the site of pacing corresponding to the site of earliest repolarization, deviating from classical restitution. In contrast, APD shortened exponentially with increasing stimulus prematurity when pacing was remote from the identical recording site. The mechanism responsible for nonexponential restitution was investigated in a one-dimensional propagation model using the dynamic Luo-Rudy formulation of the ventricular cell and was found to be attributable to depolarizing axial current present in regions of steep repolarization gradients. Moreover, axial current loading attenuated spatial gradients of repolarization that were prominent in the absence of cell-to-cell coupling. These data demonstrate that 1) in contrast to restitution in isolated cells, restitution in multicellular tissue is influenced by axial current from neighboring cells, and 2) in normal myocardium, axial current between cells attenuates dispersion of repolarization during premature stimulation of the heart.